Preparation of glucuronic acid and derivatives thereof



Patented Apr. 8, 1952 PREPARATION OF GLUCURONIC ACID AND DERIVATIVES THEREOF Dudley M. Gallagher, Berwyn, Ill., assignor to Corn Products Refining Company; New York,. N. Y., a corporation of New Jersey;

No Drawing, Application December. 8, 1949,.

Serial No. 131,930

This invention relates to the preparation of.

glucuronic acid and derivatives thereof.

The preparation of glucuronic acid fromzglur.

cose involves oxidation of the primary alcohol group of the glucose molecule. Because of the sensitivity of the aldehyde portion of the'molecule to oxidation, it is necessary that this group be protected, as by coupling it with a suitable compound, such as methyl or ethyl alcohol to provide the corresponding glucoside.

Oxidation of such protected glucose; compounds, in accordance with methods taught by the prior art, while resulting in the production of glucuronic acid, is not completelm satisiactory because such oxidants as nitric acid and nitrogen dioxide require prolonged. reaction. times, the reaction is difiicult to control within the limits required for most selective oxidation, and some hazard is inherent in the use of such oxidizing agents. Furthermore, in the case ,,of such nitrogen-containing oxidants, nitrogen compounds, are formed as a result of skiers;

actions, Which compounds, are difiicultto remove, and reduce the. overall yield. and vquality of the.

desired product.

An importantobject, therefore, of -the,.present invention is to providean improved ,prooess'ifor the. preparation. of glucuronic. acid; Another. obiectis to provide a processfor thepreparation of glucuronic acid and glucuronic acid deriva.

tiveswhich is characterized by the. use. or inexpensive materials, rapidity, and high yield.

Another object isto provide a process-for; the... production of glucuronic acid and derivatives.

thereof which utilizes. an oxidizingagent. which is safe. and a reaction system which ,is .easy to control andefiicientin operation. Still another. object is .to provide a process forthejproduc'tion of .glucuronic acid and derivatives .the'reoiowhich. utilizes an alkaline oxidizing system which is less.

corrosive than acidic oxidizing systems.

Myinvention proceeds .upon the discoverythat under certain conditions, glucose] compounds... wherein the. aldehyde group is properly protected. maybe oxidized to .the corresponding .uronicacid. derivatives. by the use. of a permanganate .salt'. as theoxidizing agent. Themethod is safe, rapid, andieconomical." and, free of, many of the. objec tionable features. of methods used heretofore;

In its broader aspects the method of-niyin; vention involves. reacting. an aqueous. solution of a. protected. glucose derivative containing... a

primary alcohoLgroup, such as, for example,

methyl; glucoside, with a permanganate. salt. in! solid. or... aqueous solution form. under alkaline 2 conditions until, reaction is complete. Completion of the reaction is indicated by the disa pearance. .of the characteristic permanganate color.

At this point, the reaction mixture is filtered. to.

remove precipitated manganese dioxide, leaving the salt of the uronic acid derivative insolutionin the filtrate The uronic. acid derivative may then befhydrolyzed to obtain the uronic acid, if-

desired;

' In accordance with my presently preferred procedure, the reaction is carried out by theconti nuous addition of an aqueous solution of sodium or potassium permanganate. to a stirred aqueoussolution'ormethyl glucoside, the reaction medium being maintained atia n alkaline pHiby the;

additionthereto of alkali in the form of ahydroxide or of a 'suitab'le'bufier salt. Generally, equivalent quantities of'reactants are used in accordance with the following:

However, the ratio of reactants maybe varied over a rather. wide range without departing :from" the scope of my invention.

In the practice of my invention, it is particu- I larly important to control the pH of the reaction media and the concentration of reactants within certain specified limits, as will be fully set forth hereinafter.

By wayof illustration of my invention, the following. specificexamples are provided; however, it-is to be'understood, thatthese examplesare illustrative only and are not intended as limiting the invention to these or any other par? ticular examples, except as may be requiredv by the-claims; appended herewith.-

Example I of 1 1-12 in the cooled (1545? c.) reaction mix ture. At. the completion of-the. oxidation, as;

indicated by the disappearance of the character istic permanganate color, the reaction mixtureis filtered to remove.manganese dioxide, yielding. a. clear. water white solution of-p'otassium methyl glucuronoside in. 61 percentyield "(150. g.)-,"in.. admixturewith other oxidation. products and .un-

. reacted methyl i lucoside. Y

Example II A number of experiments were carried out in the general manner described in Example I, except that in one case, the oxidant was added incrementally instead of continuously. Table 1 shows the effect of concentration of the glucosidic compound, temperature, time and pH.

The last experiment in the table shows the der these conditions, the reaction results in excellent yield of the desired compound in the oxidized mixture.

Insofar as reaction temperature is concerned, I have discovered that for best results, the temperature should be maintained below about 25 C. and preferably within the range of 10 C. to 25 C. Since the reaction is exothermic, the reaction vessel should be cooled by suitable means.

232 232 5 23:22: 5 ggg oxldatlon 15 The time of the reaction should be such that the permanganate is completely consumed. Genm p I erally, not more than a two hour period is re- 1,2-isopropylidene glucose was oxidized with [)3 molar solution of potassium permanganate While my invention has been descrlbed in terms in the manner described in Example I. The conof its preferred aspe 1t 15 to b understood ditions under which the 1,2-isopropylidene gluthat variations therefrom within the scop and cose was oxidized and the results obtained are Sp r t Of y invention Will S gest the sel es t set forth in Table 2. those skilled in the art.

Table 1 E Methyl Glucoside Permanganate Addition T i fi d t GIMQHWI xperi- 6111p. 0 Y 1'3. e 1101110110- meut No. 00mm 0.3 M E quivm Added Base C. Cone. Per side Per Moles Per Cent Solution lents Method Time pH Cent Cent Yield Min. 15 X14110... 1.0 5%incrle- 30 11.5 NaOH 25 4 48 men S- 10 KMnO4 1.0 continuously 25 11.5 K2003+ 3.5 48

NaOH 1o KM1104... 28 11.5 NaOH. 20 3.0 51 1o KMnO4 40 11.5 NaOH 20 2.5 49 1o KMnO4 11.0 M 051 20 3.5 47 1o KMnOr... 25 13.8 M611 3.- 10 3.5 52 1o KMn04. 43 11.5 NaOH... 10 3.5 49 10 KMHO.-- 33 11.5 Naoum. 20 3.5 53 10 KMnoim 120 11.5 NnOH 20 3.5 60 10 KMnOr..- 100 11.5 NaOH 20 3.5 a1 10 1414110.... 100 11.5 NaO 20 3.5 59 4 KMnOr... 1.5 (H5SO4) 10 3 6 l Equivalents-based upon 4KMnOi per 5ROH;OH(nO Table 2 I claim:

1. A method of preparing glucuronic acid which 1, Z-Isopropylidene comprises contacting a glucose compound con- Gluwse Equiva. Time Added taining a primary alcohol group and wherein the gg f fi Minuts PH Base aldehyde group is protected, with a permanganate Moles 35 salt in aqueous solution and at an alkaline pH, for I a time suflicient to oxidize the primary alcohol group of said glucose compound to the carboxyl 05 1O 0 2O NaOH group, and subsequently hydrolyzing the resultant glucuronic acid derivative to obtain glucuronic acid. Temperature Final Carbohydrate a fg ggg k gg 2. A method of preparing a glucuronic acid Degree) Cam-Per Cent Per Cent Yield derivative which comprises reacting a glucose compound whose aldehyde group is protected 20 a 34 against oxidation, with a permanganate salt in stoichiometrically equivalent amounts in aqueous solution and at an alkaline pH, for a time suf- In the foregoing egmples the welds of final ficient to oxidize the primary alcohol group of product were determmed by the naphthoresor- Said glucose compound to the carboxyl group and removing precipitated manganese dioxide from It is seen that one essential feature of my 60 the reaction mixture. invention is the use of a permanganate salt to A method of preparing glucuromc acid effect preferential oxidation of the alcohol group prising contacting at least one glucose compound a protected gimme F fl Wider pH from the group consisting of methyl glucoside and ditions of re1?t1ve1y.h1g.h alkahmty whereby 1,2-isopropylidene glucose with a permanganate effect an oxldaiilon the P to Its salt in aqueous solution and at an alkaline pH, g f zfi g g gi g g g g g E for a time suiiicient to oxidize the primary alcop o e r 0 Ion me m 5 Cu 6 a We hol group of said glucose compound to the cargiobzzsitdrrigfispreferably at about 11.5 01 h1gher boxyl group, and subsequently .hydrolyznllg the resultant glucuromc ac1d derivative to obtain glue The concentration of the glucose compound cumnic acid which is to be oxidized, in accordance with my A metfiod of preparing a glucuromc acid invention is preferably between about 5 Percent derivative which comprises reacting a glucose and 15 percent, in aqueous solution, when recompound containing a, primary hydroxyl group acted with a substantially equivalent amount of an wh i th aldehyde group is protected in 0.3 molar potassium permanganate solution. Unaqueous solution and at a concentration of from about 5 percent to about 15 percent, with a substantially equivalent amount of a permanganate salt, under pH conditions of relatively high alkalinity and a temperature below about 25 C. for atime sufiicient to oxidize a substantial percentage of the primary alcohol group of said glucose compound.

5. A method of preparing a glucuronic acid derivative which comprises reacting a glucoside in aqueous solution and at a concentration of from about 5 percent to about 15 percent, with a substantially equivalent amount of a permanganate salt, under pH conditions of relatively high alkalinity and at a temperature below about 25 C. for a time suiilcient to oxidize a substantial percentage of the primary alcohol group of said lucoside.

6. A method of preparing a glucuronic acid derivative which comprises reacting at least one glucose compound from the group consisting of methyl glucoside and 1,2-isopropylidene glucose in aqueous solution and at a concentration of from about 5 percent to about 15 percent, with a substantially equivalent amount of a permanganate salt, under pH conditions of relatively high alkalinity and at a temperature below about 25 C. for a period of time suflficient to oxidize a substantial percentage of the primary alcohol group of said glucose compound.

'7. A method of preparing a glucuronic acid derivative which comprises reacting 1,2-isopropylidene glucose in aqueous solution and at a concentration of from about 5 percent to about 15 percent, with a substantially equivalent amount of a permanganate salt, under pH conditions of relatively high alkalinity and at a temperature below about 25 C. for a time sufficient to oxidize a substantial percentage of the primary alcohol group of said 1,2-isopropylidene glucose.

8. A method of preparing a glucuronic acid derivative which comprises reacting methyl glucoside in aqueous solution and at a concentration of about 5 percent to about 15 percent, with a stoichiometrically equivalent amount of a permanganate salt in aqueous solution, at a pH of between about 11.0 and 14 and a temperature below about 25 C. for a. time sufiicient to oxidize a substantial percentage of the primary alcohol group of the said glucoside.

9. A method of preparing a glucuronic acid derivative which comprises reacting a glucose compound containing a primary alcohol group and wherein the aldehyde group is protected in aqueous solution and at a concentration of about 5 percent to about 15 percent, With a stoichiometrically equivalent amount of an aqueous solution of a permanganate salt, at a pH of between about 11.0 and 14, said reaction being effected at a temperature between about C. and about 25 C. by the addition of increments of said permanganate solution and continued for a period of time sufficient to oxidize a substantial percentage of the primary alcohol group of said glucose compound.

10. A method of preparing a glucuronic acid derivative which comprises reacting a glucoside in aqueous solution and at a concentration of from about 5 percent to about percent, with a stoichiometrically equivalent amount of an aqueous solution of a permanganate salt, at a pH of between about 11.0 and 14, said reaction being efiected at a temperature between about 10 C. and about 25 C. by the addition of increments of said permanganate solution and allowed to proceed for a period of time sufiicient to oxidize 6 a substantial percentage of the primary alcohol group of said glucoside. I

11. A method of'preparing a glucuronic acid derivative which comprises reacting at least one glucose compound from the group consisting of methyl glucoside and 1, 2-'-isopropylidene glucose in aqueous solutionand at a concentration of from about 5 percent to about 15 percent, with a stoichiometrically equivalent amount of an aqueous solution of a permanganate salt, at a pH of between about 11.0 and 14, said reaction being effected at a temperature between about 10 C. and 25 C. by the addition of increments of said permanganate solution and allowed to proceed for a period of time sufiicient to oxidize a substantial percentage of the primary alcohol groups of said glucose compound.

12. A method of preparing a glucuronic acid derivative which comprises reacting 1,2-isopropylidene glucose in aqueous solution and at a concentration of from about 5 percent to about 15 percent, with a stoichiometrically equivalent amount of an aqueous solution of a permanganate salt, at a pH of between about 11.0 and 14, said reaction being efiected at a temperature of between about 10 C. and about 25 C. by the addition of increments of said permanganate solution and allowed to proceed for a period of time sufiicient to oxidize a substantial percentage of the primary alcohol group of said 1,2-isopropylidene glucose.

13. A method of preparing a glucuronic acid derivative which comprises reacting an aqueous solution of methyl glucoside having a concentration of from about 5 percent to about 15 percent, with a substantially equivalent amount of an aqueous solution of a permanganate salt, said reaction being effected at a temperature between about 10 C. to about 25 C. by the addition of increments of said permanganate solution and allowed to proceed for a period of time sufficient to oxidize a substantial percentage of the primary alcohol groups of said methyl glucoside.

14. A method of preparing a glucuronic acid derivative which comprises reacting at least one glucose compound from the group consisting of methyl glucoside and 1,2-isopropylidene glucose in aqueous solution and at a concentration of from about 5 percent to about 15 percent, with a substantially equivalent amount of an aqueous solution of a permanganate salt, said reaction being eifected at a temperature between about 10 C. to about 25 C. by the continuous addition of said permanganate solution and over a period of time sufiicient to oxidize a substantial percentage of the primary alcohol group of said glucose compound.

15. A method of preparing a glucuronic acid derivative which comprises reacting methyl glucoside in aqueous solution and at a concentration of from about 5 percent to about 15 percent. with a substantially equivalent amount of an aqueous solution of a permanganate salt, said reaction being effected at a temperature between about 10 C. to about 25 C. by the continuous addition of said permanganate solution and over a period of time sufiicient to oxidize a substantial percentage of the primary alcohol group of said methyl glucoside.

16. A method of preparing a glucuronic acid derivative which comprises reacting 1,2-isopro-'- pylidene glucose in aqueous solution and at a concentration of from about 5 percent to about 15 percent with a substantially equivalent amount of an aqueous solution of a permanganate salt,

7 8 said reaction being effected at a. temperature between about 10" c. to about 25 c. by the con- FEFERENCES CITED tm addition of said permanganate solution The followmg references are of record 1n the and over a period of time sufficient to oxidize a file Of this P substantial percentage of the primary alcohol 5 Pi Chemistry of carbohydrates roup of said 1,2-isopropy1idene glucose. 334, 339, 341, Academic Press Ine N. Y 1948.

DUDLEY M. GALLAGHER. 

1. A METHOD OF PREPARING GLUCURONIC ACID WHICH COMPRISES CONTACTING A GLUCOSE COMPOUND CONTAINING A PRIMARY ALCOHOL GROUP AND WHEREIN THE ALDEHYDE GROUP IS PROTECTED, WITH A PERMANGANATE SALT IN AQUEOUS SOLUTION AND AT AN ALKALINE PH, FOR A TIME SUFFICIENT TO OXIDIZE THE PRIMARY ALCOHOL GROUP OF SAID GLUCOSE COMPOUND TO THE CARBOXYL GROUP, AND SUBSEQUENTLY HYDROLYZING THE RESULTANT GLUCURONIC ACID DERIVATIVE TO OBTAIN GLUCURONIC ACID. 